Abstract: Huntington?s disease (HD) is a hereditary, neurodegenerative disorder caused by a triplet repeat (CAG) expansion in exon 1 of the Huntington (HTT) gene. Although HD typically starts in adulthood, higher CAG repeat numbers produce a shift in disease onset which can start in juveniles and even infants. Juvenile HD is more severe than adult-onset HD and the symptoms, including rigidity, mental retardation, and seizures differ from those typical of adult-onset HD, namely chorea (uncoordinated dance-like movements), cognitive deficits, and mood swings. These symptoms are caused by cell dysfunction and loss primarily in striatum and cerebral cortex. Recent studies have demonstrated that wildtype huntingtin (Htt) is essential for proper cortical development and the presence of the mutant form (mHtt) leads to abnormal cytoarchitecture of the cerebral cortex. However, at present nothing is known about the early development of cortical and striatal morphological and functional abnormalities in HD. The present study will determine how early during brain development aberrant cell membrane properties and synaptic communication can be detected in cortical and striatal projection neurons. Particular emphasis will be placed on trying to understand the origin and mechanism of cortical hyperexcitability in HD, as well as finding methods to restore normal function. Specifically, we hypothesize that in HD calcium signaling in cortical pyramidal neurons is disturbed during cortical development leading to aberrant cytoarchitecture and hyperexcitability. The proposal has two specific aims; aim 1 will test the hypothesis that the presence of mHtt leads to abnormal morphological and electrophysiological development of the cerebral cortex in two mouse models of HD, the R6/2 (a model of juvenile HD) and the Q175 (a model of adult-onset HD), and aim 2 will test the hypothesis that abnormal cortical development leads to aberrant corticostriatal synaptic transmission in HD mice. To accomplish these goals we will use an array of morphological, electrophysiological and imaging techniques. These studies will provide mechanistic insights into disease progression and will help identify early and specific therapeutic targets.